The mechanisms by which T cells contribute to host immunity against intracellular infections, as in leprosy and tuberculosis, remain unclear. Leprosy, caused by the intracellular pathogen Mycobacterium leprae (mLEP), predominantly localized to skin, represents an accessible model to investigate human immune responses to intracellular bacterial infection. The clinical manifestations of leprosy form a spectrum, which correlates with the immune response to the pathogen. Patients with tuberculoid leprosy (T-lep) develop protective immunity to wall off and eliminate the infection, whereas those with lepromatous leprosy (L-lep) sustain a disseminated and progressive infection. This proposal is based upon the premise that traditional human Th1 T cells are not sufficient for protection against mycobacterial disease and that characterization of molecular mechanisms and markers of other antimicrobial T cell populations may lead to unique biomarkers of protective immunity, critically needed to develop protective vaccines. Our preliminary data identify two novel antimicrobial T-cell subpopulations, both bearing innate receptors that contribute to protective immunity against intracellular mycobacteria, and directly or indirectly capable of reducing viability of mLEP and other pathogens. First, a subpopulation of CD8+ cytolytic T lymphocytes (CTLs) that express a specific NK receptor can be triggered by that innate receptor to release the anti-mycobacterial protein granulysin (GNLY). Second, a subpopulation of CD4+ Th17 cells that express IL-1RI can be triggered by IL-1? to secrete the antimicrobial protein IL-26. Notably, neither GNLY nor IL-26 exists in mice. We hypothesize that innate receptors on human CD4+ and CD8+ T-cell subpopulations, in addition to T cell receptors (TCRs), can be directly activated to induce the release antimicrobial effector molecules that contribute to host defense against intracellular pathogens. We propose to identify molecular markers of CD4+ and CD8+ antimicrobial T-cell subpopulations, facilitating investigation of the mechanisms by which those cells are induced, activated and able to reduce the viability of intracellular pathogens. Our specific aims are to: 1) Elucidate mechanisms by which CD8+ CTLs are triggered via innate receptors to mediate an antimicrobial response, 2) Define mechanisms by which CD4+ Th17 cells mediate antimicrobial activity, and 3) Identify the innate pathways that induce antimicrobial T-cell differentiation in leprosy. The identification of antimicrobial T cell mechanisms and potential functional biomarkers will facilitate new strategies for monitoring protective responses, evaluating new vaccine candidates and therapeutic interventions against diseases caused by intracellular bacteria.